Guanine-rich sequences show large structural variability, with folds ranging from duplex to triplex and quadruplex helices. Quadruplexes are polymorphic, and can show multiple stoichiometries, parallel and antiparallel strand alignments, and different topological arrangements. We analyze here the equilibrium between intramolecular antiparallel and intermolecular parallel G-quadruplexes in the thrombin-binding aptamer (TBA) sequence. Our theoretical and experimental studies demonstrate that an apparently simple modification at the loops of TBA induces a large change in the monomeric antiparallel structure of TBA to yield a parallel G-quadruplex showing a novel T-tetrad. The present results illustrate the extreme polymorphism of G-quadruplexes and the ease with which their conformation in solution can be manipulated by nucleotide modification.